Method of producing pyrrolidinones

专利摘要:
The invention relates to substituted pyrrolidinones (RFP) of the common formula of RjCH2-CH-NH-C (0) -CR, where R, is H, or C, is C-alkyl; or iso-C4-alkyl or phenyl; Rj is thienyl-2; phenyl (it can be substituted with halogen, CHJ or CFj, or dihalogen, the same or different, or dimethoxy groups), which have an effect on the central nervous system. The goal is to create iovyh more active substances of the specified class. Their synthesis is carried out by cyclization of t, α-amino ester of the total f-lg K CH - CH (NHg) CHg-CR, -C (0) -0-Alc, where Alk is lower alkyl; R, - R, are indicated above. New substances have an effect on spontaneous motor ability at a dose of 100 mg / kg to 99%, on potentiation of anesthesia in pentobarbitel up to 80%, on convulsive - my effect on electric current at a dose of 91-108 mg / kg, on convulsive and lethal antagonism caused biculine, at a dose of 33-240 mg / kg. 7 tab. i SU) with
公开号:SU1391497A3
申请号:SU843764652
申请日:1984-07-11
公开日:1988-04-23
发明作者:Бизьер Катлин；Шамбон Жан-Пьер；Молимар Жан-Шарль
申请人:Санофи (Фирма)；
IPC主号:

专利说明:

with so

with vj
 CM
 I391a97
The invention relates to the field of production of new pyrrolidinones of the general formula
n
ln s l
R2
p4-r.
HoCA 0

n
Where
R,
R, R, hydrogen or s, - C, -alkyl; straight or branched C, -C-alkyl or phenyl; thienyl-2, unsubstituted phenyl or phenyl substituted with one halogen atom, methyl or trifluoromethyl, or phenyl substituted with two halogen atoms with the same or different, or two methoxy groups,
actively acting on the central nervous system.
The aim of the invention is to develop, based on the known methods of the method of obtaining new compounds, which possess valuable pharmacological properties.
Example 1. H-ethyl-5 - (2-fluoro-phenyl) methyl-3-methyl-2-pyrrolidinone; R 42001.
but. 4-keto-2 ethyl-5- (2-fluorophenyl) -2-methylvaleric acid ethyl ester.
Dissolve 18.5 g of sodium in 250 ml of absolute ethyl alcohol, then add 11 O g of dimethyl diester 2-ethyl-2-methyl succinic acid and 72 g of benzyl 2-fluorocyanide
Under reflux, incubate for 6 hours with stirring, then stir overnight at room temperature.
After evaporation of the solvent, 500 ml of water are added and then extracted with 2 times 500 ml of ether. The aqueous phase is acidified to pH 4 with acetic acid, then extracted with chloroform, dried over sodium sulfate, and the solvent is evaporated under vacuum. 235 ml of water, 775 ml of acetic acid and 260 ml of KOH) of concentrated hydrochloric acid are added to the residue, then the solution is heated with a reflux condenser for 11 hours and nitrogen atmosphere, then the solution is evaporated in vacuo, added g of dichloroethane, washed with water.


five
0
five
0
five
0
the organic phases are dried over sodium sulfate and concentrated in vacuo.
300 ml of absolute ethanol is added to the residue with 6 ml of concentrated sulfuric acid, then heated under reflux for 24 hours. After evaporation of the ethanol, it is extracted with dichloroethane, washed with water, saturated sodium chloride solution and dissolved over sodium sulfate.
63 g of 4-keto-2-methyl-5- (2-fluorophenyl) -2-methyl-valeric acid ethyl ester are obtained.
at. 2-ethyl-5- (2-fluorophenyl) -2-methyl-4-hydroxyimino-maleic acid ethyl ester.
63 g of the α-ketosfere prepared above is dissolved in 360 ml of 96% ethanol (by volume) and 125 mg of water. 19 g of hydroxylamine hydrochloride and 35 g of anhydrous sodium acetate are added. Heat with a reflux condenser for 11 hours. After evaporation, the solution is extracted with dichloromethane, rinsed with water, saturated sodium chloride solution, then dissolved over sodium sulfate. The solvent is evaporated in vacuo, then the residue is chromatographed with 600 g of silica with an ethyl l-pentane acetate mixture (25/75 vol).
20 g of ethyl 2-ethyl-5- (2-fluorophenyl) -2-methyl-4-hydroxyiminoBaleric acid are obtained.
with. SR 42001.
20 g of the oxime obtained above is placed in an autoclave. 100 ml of 90% acetic acid and 10 g of 5% platinum on carbon are added.
soda
The hydrogenation is carried out under a pressure of 20 atm., |, At ordinary temperature for 10 hours. After filtering on Hyflocell, the solvent is evaporated, the residue is taken up with water, concentrated caustic is added
pH 11 without cooling. After 15 minutes, it is extracted with dichloromethane, washed with water, then with a saturated solution of sodium chloride, dried over sodium sulfate, then evaporated in vacuo. The residue is chromatographed with 250 g of silica; eluant is a mixture of dichloromethane and ethyl acetate (60-40 vol).
The resulting product is distilled, b.p. 175-180 C, with 0.01 mm Hg; 1.5 g of the desired product are obtained.
Example 2. 5-f (4-fluorophenl) -methyl-3-methyl-2-pyrrolidinone: SR 41882.
but. 4-keto-5-f4-fluorophenyl J-2-methylvaleric acid ethyl ester.
They work as in Example 1 and with the same quantities, but starting from benzyl p-fluorocyanide and methyl diester 2-methyl succinic acid.
The complex Cf-ketoester thus obtained is distilled under vacuum, b.p. 120-130 With at 0.05 mm Hg. 42 g of product is recovered.
at. SR 41882.
42 g of the product obtained above are dissolved in 800 ml of methanol, 145 g of ammonium acetate is added, followed by 7.8 g of sodium cyanoborohydride. After stirring for 16 hours, 3/4 of the solution was evaporated in vacuo, then 400 ml of water was removed, 200 mg of acetic acid was added, and then stirred for 1 hour before neutralizing with acidic sodium carbonate. Then the pH is adjusted to 11 by adding 30% alkali, the temperature is raised to
After 15 minutes of stirring, it is taken up in dichloromethane, washed, dried over sodium sulfate and evaporated in vacuo, then dried again for 1 hour at 90 ° C in vacuo. The resulting 30 g is chromatographed with 700 g of silica using pure ethyl acetate as eluant.
After concentration with isopropyl ether, 13 g of the expected product are obtained, m.p. .
PRI me R 3. 3, 3-Dimethyl-5- (4-fluorophenyl) -mettes J-2-pyrrolidinone: SR 41293.
This product is obtained according to the method described in Example 2. After recrystallization in cyclohexane, m.p. 114 ° C.
EXAMPLE 4: 3-methyl-5- (2-tyenylmethyl) -2-pyrrolidinone, the trans isomer (SR 42008); cis isomer (SR 42009
but. Methyl ester of 2-methyl-4-nitro 5-thienylvaleric acid.
To a solution of 23 g of 2-nitrovinylthiophene in 200 ml of dimethyl sulfoxide was added 21 g of methacrylate. Keeping the temperature while stirring
0
five
0
five
0
five
0
five
0
five
between 23 and 30 ° C., parts of 2.82 g of sodium borohydride are added in a slug.
After 14 hours of stirring, I5 ml of water and 30 ml of acetic acid are added, poured into 1 liter of ice water, then stirred for 30 minutes, extracted 5 times with 300 ml of ether, then washed 3 times with 400 ml of water, 1 times with 400 ml of saturated sodium chloride solution , dried over sodium sulfate, then the ether is evaporated in vacuo. The residue is chromatographed with 800 g of silica using a mixture of pentate and ethyl acetate (80/20 by volume) as eluant.
2 diastereoisomers of the nitroester are obtained.
at. SR 42008.
4.5 g of the nitro ester, the least polar, are hydrogenated in 500 ml of 95% ethanol with Rene T1 nickel (I tsp under a pressure of 10 atm. For 24 h.
Filter on Hyflocell, add solvent, then recrystallize. There are in cyclohexane. 1.5 g of the trans isomer of the desired product are obtained: SR 42008; m.p. 97 ° C.
with. SR 42009.
4.2 g of the most polar nitro ester are hydrogenated under the same conditions to obtain 1.6 g of the cis isomer:
SR 42009; m.p. 117 ° C, after recrystallization in cyclohexane. The cis-isomer identification is carried out by nuclear NMR overhauser.
Similarly to the examples given, the compounds listed in Table 2 were prepared. one .
The effects of compounds on the central nervous system are measured by various pharmacological tests. For each of these tests, the effects of phenylmethyl-5-pyrrolidinone-2 (compound A) were measured.
The effect of compounds on spontaneous motor ability is shown in table 2.
The equipment consists of an actimetric cell, such as Apclab (26 x X 21.5 X 10 cm), intersected by two light rays incident on a photovoltaic cell. The compartments are filled with CDL female mice weighing between 20 and 24 g of Charles Rivers' mice. Animals are placed individually in cages 45 minutes after oral administration of the product at a dose of 100 mg / kg. Each intersection of the light beam is recorded by a personal counter. The amount corresponding to the movements of the animals is recorded for 10 minutes and compared with the number of movements of the part of the animals that serve as the standard, which only solvent was prescribed (gum arabic 5%)
After taking oral1. By 100 mg / kg dosage, some products of the invention cause arousal of motor activity in mice (SR 416/8, SK, SR 4188), while others have a soothing effect. and the ability of animals to be reduced (SR 41676, SR 42008, SR 42009).
Compound A does not affect the mobility of animals.
Anesthesia potentiation in pento-barbital is shown in Table 3,
In order to evaluate the hypnogenic effect of the products, their ability to potentiate the effects of the superadrug of pentobarbital in mice is studied. The divisions consisted of 10 of our CDL weights ranging from 20-24 g. To Charles Rivers.
Pentabarbtal (20 mg / kg, L.V) was announced 60 cues after using the product. The criterion for delayed arrest is the loss of the sharp behavior change reflex. Animals in which this reflex was not observed .; rewritten.
The products according to the invention are capable of potentiating anesthesia with pentobarbital, this property foreshadows a hypnogenic effect. Compound A does not have a hypotensive-I effect.
Evaluation of anti-tonic effects of products.
The anticonvulsant effect of the products on mice was determined from a convulsive model with an effect produced by an electrically-current, and on 2 convulsive models with effects from chemical agents: bicculin and 3-mercaptopropionic acid.
but. Convulsive antagonism under the action of electric current is shown in Table 4.
The test material consists of a Racia shock generator fitted with 2
S
0
0
0
five
0
five
ocular malleability n, giving a current of 60 V and a current of 0.3 s. The departments consisted of 1 CDL of Charles Rivers weighing between 20-24 g. The products were pre-recorded by oral route 60 minutes before an electric shock. Animals in which no tonic distribution of the hind limbs was observed were interpreted as protected from an attack of an AI.
at,. Convulsive and mortal antagok.izm, vyzuee th bikukulin, shown in tab.Z.
The departments consisted of 10 (Fgshey Charles Rivers CDL weighing in the range of 20-22 g. Products of g / o / ralg (60 60 by MivH before using bicululin 0.8, iv). The occurrence of tonic convulsions and mortality was noted in 60 minutes immediately after the injection of bickey.
with Convulsive antagonism caused by 3-mercaptopropionic acid, is shown in Table 6.
Lungs consisted of 0 Charles Rivers CDL mice weighing between 20-22 g. Products were prescribed by oral route 60 minutes before taking Z-mercaptopropionic acid (60 mg / kg, S.C). Tonics and convulsions were noted for 60 minutes immediately after the use of 3-mercaptoproptic acid.
After ingestion of oral products by the mouse, they according to the invention exhibit anticonvulsant properties in the case of both electroshock and the action of bicculin and 3-mercaptopropionic acid. On the contrary, compound L does not exhibit anti-convulsive properties.
The toxicity of the products according to the claims has also been studied; products were prescribed by oral route of lots of females, 5 mice of Charles Rivers CDL weighing between 20-24 hours. Toxicity was noted for 72 hours immediately after taking the products.
The results are shown in table 7.
Experimental results in percentage of animals that died 72 hours after oral administration of the products are noted in Table 6.
Legal doses are significantly increased compared with the active doses in the described pharmacological tests.
The experiments thus carried out show that the products according to the invention exhibit interesting and slightly toxic pharmacological properties.

权利要求:
Claims (1)
[1]
two methoxy groups. Claim 10 wherein
u-aminated ester
formulas
The method of obtaining pyrrolidinone general formula
Rz r-4-ri
n
where R, is hydrogen or C -, - C4-alkyl; R 7 straight or branched C, - C4 alkyl or unsubstituted phenyl;
R,
15
РЗ-ШЗ-СН-СН - С-С-ОА1К
Jh
RO o
20
where RJ is the indicated value,
Alk is lower alkyl; subjected to cyclization.
- thienyl-2, unsubstituted phenyl ishy, phenyl substituted by one halogen atom, methyl or trifluoromethyl, or phenyl substituted by two halogen atoms, the same or different, or
R,
15
РЗ-ШЗ-СН-СН - С-С-ОА1К
Jh
RO o
where RJ is the indicated value,
Alk is lower alkyl; subjected to cyclization.
Table I
iPr70 - isopropyl ether.
Motor activity (number of movements from reference animals),%
SR 41676 SR 41678 SR 41680 SR 41881 SR 42008 SR 42009 Connection
p or equal to 0.05 p or equal to 0.01.
41293
41676 41677
80 (DE 50 - 56 (47-85)
100 (DE 50 49 (35-66) 30
Continuation of table 1
Table 2
-34 +45 +99
+41
#
-52
-23 + 1.2
Table3
Continuation of table 3
The DE 50 is calculated by the probability method and the increment in brackets is set to a probability level of P or 0.05,
Table
Products
SR 41293 SR 41676 SR 41678
Table
An effective average dose (DE 50) of convulsive antagonism, induced by the action of 3-mercaptopropionic acid (mg / kg per os)
20 (17-23) 23 (18-29) 53 (38-75)
The DE 50 is calculated by the probability method and the confidence interval in parentheses is set for a probability level of p f or 0.05.
Spreadsheets
 591D9716
Continued tbl.6
17
1391497
18 Continuation of table 7

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法律状态:

优先权:

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